Effects of Fatty Acid Synthase Inhibition by Orlistat on Proliferation of Endometrial Cancer Cell Lines

Wysham, Weiya Z.; Roque, Dario R.; Han, Jianjun; Zhang, Lu; Guo, Hui; Gehrig, Paola A.; Zhou, Chunxiao; Bae‐Jump, Victoria L.

doi:10.1007/s11523-016-0442-9

Cited by 37 publications

(23 citation statements)

References 34 publications

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“…Consistent to previous reports, our current data also indicated that GDM significantly enhances the harmful lipid levels both in plasma and in liver. ACC was reported to provide the malonyl-CoA as a substrate for the biosynthesis of fatty acids [ 43 ]. Our data indicated that phosphorylations of ACC in GDM groups were significantly inhibited, while total ACC protein levels were increased, implying that the ACC activity was enhanced in GDM state.…”

Section: Discussionmentioning

confidence: 99%

Combined intervention of swimming plus metformin ameliorates the insulin resistance and impaired lipid metabolism in murine gestational diabetes mellitus

Huang

Yue

et al. 2018

PLoS ONE

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Gestational diabetes mellitus (GDM) has short- and long- term influence on pregnant women and fetus. Swimming, as an aerobic exercise, can effectively improve the blood glucose level in GDM, but the effect of mild swimming alone was not very substantial. Metformin, as an oral antidiabetic drug, has obvious hypoglycemic effect, and is economic also, but the long-term effect on pregnant women and fetus has not been completely clear. We hypothesize that combined intervention of mild swimming and low dose of metformin, may effectively reduce blood glucose, improve the pregnancy outcomes in GDM dams, but simultaneously avoiding the adverse effects caused by overdose of drug and impotence of mild swimming. The streptozotocin was used to stimulate C57BL/6J mice to develop GDM, by which serum glucose, TC, TG, LDL-C were increased significantly, meanwhile HDL-C was decreased significantly in the GDM control (DC) group compared with the normal control group. Swimming or metformin intervention slightly or moderately improves hyperglycemia, insulin sensitivity and lipid metabolism both in liver and skeletal muscle from GDM mice, while combined therapy of swimming plus metformin markedly ameliorated hyperglycemia (FPG, decreased by 22.2–59.5% from G10 to G18 versus DC group), insulin sensitivity (2.1 and 2.8 fold increase, respectively, in AKT activity versus DC group) and de novo lipogenesis (3.2 and 7.0 fold decrease, respectively, in ACC activity, and 1.94 and 5.1 fold decrease, respectively, in SREBP2 level, versus DC group) both in liver and skeletal muscle from GDM mice. We conclude that the combined intervention by metformin plus swimming may be more effective than single action to ameliorate glucose and lipid metabolism via improving insulin sensitivity in GDM mice.

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Section: Discussionmentioning

confidence: 99%

Combined intervention of swimming plus metformin ameliorates the insulin resistance and impaired lipid metabolism in murine gestational diabetes mellitus

Huang

Yue

et al. 2018

PLoS ONE

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“…ACC, as the rate limiting enzyme, plays a vital role in the synthesis of fatty acid, mainly phosphorylated by the upstream factor p-AMPK to inhibit fatty acid activation and promote fatty acid oxidation to achieve the reduction of the fatty acid synthesis [ 33 – 36 ]. By evaluating the alterations of placenta glucose and fatty acid metabolism related factors, we found that the mRNA and phosphorylation of ACC in GDMM group were significantly inhibited.…”

Section: Discussionmentioning

confidence: 99%

GDM-Induced Macrosomia Is Reversed by Cav-1 via AMPK-Mediated Fatty Acid Transport and GLUT1-Mediated Glucose Transport in Placenta

et al. 2017

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ObjectiveTo investigate if the role of Cav-1 in GDM-induced macrosomia is through regulating AMPK signaling pathway in placenta.MethodsWe used diagnostic criteria of gestational diabetes mellitus (GDM) and macrosomia to separate and compare placental protein and mRNA levels from GDM with macrosomia group (GDMM), GDM with normal birth weight group (GDMN) and normal glucose tolerance (NGT) with normal birth weight group (CON). Western blotting was performed to examine differentially expressed proteins of caveolin-1 (Cav-1) and Adenosine monophosphate-activated protein kinase (AMPK) signaling pathway related proteins, including phosphorylated-AMPKα(Thr172), AMPKα, phosphorylated-Acetyl-CoA carboxylase(Ser79) (p-ACC(Ser79)), ACC and glucose transporter 1 (GLUT1) in placenta between the three groups. The mRNA levels of Cav-1, AMPKα, ACC and GLUT1 in placenta were measured by real time-PCR.ResultsIn the GDMM placenta group, both protein and mRNA levels of Cav-1 were down-regulated, while GLUT1 was up-regulated; the phosphorylation and mRNA levels of ACC and AMPKα were decreased, but total ACC protein levels were increased compared to both the GDMN (p<0.05) and CON groups (p<0.05). In GDMM placenta group, there was a significant negative correlation observed between neonatal birth weight (NBW) and protein expression levels of Cav-1, p-ACC(Ser79) and p-AMPKα(Thr172) (p<0.05), while positive relationship with ACC and GLUT1 protein levels. Besides, in GDMM group placental mRNA levels, NBW had a positive correlation with GLUT1 (p<0.05), while negative with Cav-1, AMPKα and ACC expression (p<0.05). Cav-1 protein expression was positively associated with p-AMPK and p-ACC (p<0.05), and negatively associated with GLUT1 (p<0.05). Interestingly, p-AMPK protein expression was closely related to p-ACC (p<0.05), but not with GLUT1.ConclusionGDM-induced macrosomias have more severe inhibition of Cav-1 expression in placenta. Cav-1 is associated with placental glucose and fatty acid transport via the induction of AMPK signaling pathway and the reduction of GLUT1 signaling pathway to reverse GDM-induced macrosomia.

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“…It shows promising inhibitory effect on cell proliferation as well as tumor growth in prostate and breast cancer cells. 22 The finding that orlistat could reduce the uptake of 18 F-FPA by up to 42.7% in HCC cells indicated the important role of FASN in 18 F-FPA uptake. In accordance with the results of immunofluorescence and proteomic analyses, the expression of FASN was in the same order which may help explain the mechanism of 18 F-FPA uptake.…”

Section: Discussionmentioning

confidence: 94%

PET Imaging of Hepatocellular Carcinomas:¹⁸F-Fluoropropionic Acid as a Complementary Radiotracer for¹⁸F-Fluorodeoxyglucose

et al. 2019

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Objective:To evaluate the preclinical value of 18F-fluoropropionic acid (18F-FPA) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) for imaging HCCs.Methods:The 18F-FPA and 18F-FDG uptake patterns in 3 HCC cell lines (Hep3B, HepG2, and SK-Hep1) were assessed in vitro and in vivo. The 18F-FPA uptake mechanism was investigated using inhibition experiments with orlistat and 5-tetradecyloxy-2-furoic acid. The 18F-FPA PET imaging was performed in different tumor animal models and compared with 18F-FDG. We also evaluated the expressions of glucose transporter-1 (GLUT1), fatty acid synthase (FASN), and matrix metalloproteinase-2 (MMP2) in these cell lines.Results:In vitro experiments showed that the radiotracer uptake patterns were complementary in the HCC cell lines. Orlistat and 5-tetradecyloxy-2-furoic acid decreased the uptake of 18F-FPA. The tumor-to-liver ratio of 18F-FPA was superior to that of 18F-FDG in the SK-Hep1 and HepG2 tumors (P < .05). However, in the Hep3B tumors, the tumor-to-liver normalized uptake of 18F-FDG was higher than 18F-FPA (P < .01). FASN was highly expressed in cell lines with high 18F-FPA uptake, whereas GLUT1 was highly expressed in cell lines with high 18F-FDG uptake. The 18F-FPA uptake correlated with FASN (r = 0.89, P = .014) and MMP2 (r = 0.77, P = .002) expressions.Conclusions:PET imaging with 18F-FPA combined with 18F-FDG can be an alternative for detecting HCC.

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Effects of Fatty Acid Synthase Inhibition by Orlistat on Proliferation of Endometrial Cancer Cell Lines

Cited by 37 publications

References 34 publications

Combined intervention of swimming plus metformin ameliorates the insulin resistance and impaired lipid metabolism in murine gestational diabetes mellitus

Combined intervention of swimming plus metformin ameliorates the insulin resistance and impaired lipid metabolism in murine gestational diabetes mellitus

GDM-Induced Macrosomia Is Reversed by Cav-1 via AMPK-Mediated Fatty Acid Transport and GLUT1-Mediated Glucose Transport in Placenta

PET Imaging of Hepatocellular Carcinomas:¹⁸F-Fluoropropionic Acid as a Complementary Radiotracer for¹⁸F-Fluorodeoxyglucose

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Effects of Fatty Acid Synthase Inhibition by Orlistat on Proliferation of Endometrial Cancer Cell Lines

Cited by 37 publications

References 34 publications

Combined intervention of swimming plus metformin ameliorates the insulin resistance and impaired lipid metabolism in murine gestational diabetes mellitus

Combined intervention of swimming plus metformin ameliorates the insulin resistance and impaired lipid metabolism in murine gestational diabetes mellitus

GDM-Induced Macrosomia Is Reversed by Cav-1 via AMPK-Mediated Fatty Acid Transport and GLUT1-Mediated Glucose Transport in Placenta

PET Imaging of Hepatocellular Carcinomas:18F-Fluoropropionic Acid as a Complementary Radiotracer for18F-Fluorodeoxyglucose

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PET Imaging of Hepatocellular Carcinomas:¹⁸F-Fluoropropionic Acid as a Complementary Radiotracer for¹⁸F-Fluorodeoxyglucose